A paradigm shift for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer: a review of CDK inhibitors

Abstract

In the last 3 years, a novel class of targeted therapy has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. There are currently three approved agents, which are oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. All of the approved drugs exhibit progression-free survival benefit when compared to standard of care and generally have less adverse events compared to traditional chemotherapeutic options. The treatment of HR+/HER2− advanced breast cancer is a continuously evolving landscape, and the addition of CDK4/6 inhibitors is the newest mechanism for treatment. In this review, we summarize all available data, highlight the unanswered questions, and discuss pharmacological differences between each CDK4/6 inhibitor.

Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes

“…The first CDK4/6‐specific inhibitor, palbociclib (PD‐0332991), was reported in 2004 3,4 . Over the next decade, the next CDK4/6 specific inhibitors ribociclib (LEE011) and abemaciclib (LY‐2835219) were developed, 5‐7 and many clinical trials have been performed for various neoplasia including non–small‐cell lung cancer, colon cancer, and breast cancer 8,9 . These inhibitors have been approved for breast cancer therapy by the FDA and the corresponding agencies in other countries 8,9 .…”

“…3,4 Over the next decade, the next CDK4/6 specific inhibitors ribociclib (LEE011) and abemaciclib (LY-2835219) were developed, [5][6][7] and many clinical trials have been performed for various neoplasia including non-small-cell lung cancer, colon cancer, and breast cancer. 8,9 These inhibitors have been approved for breast cancer therapy by the FDA and the corresponding agencies in other countries. 8,9 In terms of the therapeutic mechanism in cancer cells, these inhibitors block CDK4/6-cyclin D activity, leading to inhibition of Rb phosphorylation, which represses transcription of the genes associated with the G 1 /S transition.…”

“…8,9 These inhibitors have been approved for breast cancer therapy by the FDA and the corresponding agencies in other countries. 8,9 In terms of the therapeutic mechanism in cancer cells, these inhibitors block CDK4/6-cyclin D activity, leading to inhibition of Rb phosphorylation, which represses transcription of the genes associated with the G 1 /S transition. 10 Thus, these inhibitors are considered to induce a cytostatic effect, rather than a cytocidal effect, in cancer cells.…”

PALOMA-3 clinical trial: is there a significant benefit in overall survival for breast cancer? Is it worth it?

“…Several patients are diagnosed and follow to a progressive disease every year. CDK4/6 inhibitors (CDKi) were a paradigm shift in the treatment of hormone receptor-positive (HR+), HER2-negative advanced breast cancer (aBC) [1].…”

“…Without a randomized controlled trial to compare the three FDA-approved CDKi head to head, it is uncertain if there is any significant difference between the efficacies of these agents -albeit, these agents seem to have similar efficacies. It seems as though the biggest differences between these drugs lies within their adverse event profiles due to varying molecular structures and off-target interactions [1].…”